Advertisement

Advertisement

BIG PHYSICS, BIG QUESTIONS –

Synthetic poison comes in with the tide

By David Bradley

AFTER what they describe as a twelve-year odyssey, a team of chemists in California has made one of the natural poisons that makes “red tides” so deadly. Red tides occur when there is a sudden population explosion among certain microscopic algae living in coastal waters. The toxins help to protect the algae from being eaten, but huge numbers of fish and marine mammals can be killed by red tides, and anyone unlucky enough to eat contaminated seafood can be poisoned. Some waters, such as Tolo Harbour in Hong Kong, are hit by the tides every year.

The chemists’ quest was for a synthetic version of the most important of the toxins, brevetoxin B, produced by an alga called Gymnodinium breve. Their efforts could ultimately help in the search for antidotes to treat red tide poisoning and tests to determine whether seafood is safe to eat.

Red tides have been recorded since Biblical times, but in the past 20 years they have become more common, possibly because agricultural fertilisers and other pollutants are finding their way into coastal waters and providing better growing conditions for the algae. Aside from their devastating environmental effects and the danger to human health, red tides inflict millions of pounds’ worth of damage on the shellfish industry.

Scientists would like to devise antidotes to red tide poisoning, or at least produce simple tests to determine whether or not seafood is dangerously contaminated. But to do this, they need to have large quantities of the toxin to study in the laboratory. The problem has been that brevetoxin B is very difficult to extract from the complex mixture of chemicals produced by Gymnodinium breve.

Advertisement

Twelve years ago the Californian chemists, led by Kyriacos Nicolaou of the Scripps Research Institute in La Jolla and the University of California, San Diego, realised that the best way around this problem would be to make the poison in the laboratory. Since then, Nicolaou’s team has struggled to find a way of building brevetoxin B’s complex molecular structure. Along the way, they have invented several methods for putting chemical jigsaws together that could help other chemists make novel pharmaceuticals, agrochemicals, plastics and cosmetics. Now the researchers have achieved their goal. They report their success in the Journal of the American Chemical Society (vol 117, p 1171).

Brevetoxin B is made up of 11 rings of carbon and oxygen atoms fused together, with various chemical groups attached. The molecule also has 23 “stereocentres” – carbon atoms that can be joined to other chemical groups in more than one orientation. Nicolaou’s team tackled this complexity by working backwards from the known chemical structure of brevetoxin B, thinking of reactions that would convert it into simpler chemicals that are available “off the shelf”. They then tried to manufacture the poison by running these reactions in reverse.

The team eventually decided to start from a chemical called 2-deoxy-D-ribose, which forms the sugar backbone of DNA. Getting from this compound to brevetoxin B involved 83 chemical reactions. The main difficulty was finding the correct sequence in which to close the molecule’s 11 rings. For many of the sequences the researchers tried, it was impossible to close the final ring. “That’s why it took us twelve years,” says Nicolaou.

Each step in the synthetic pathway is very efficient and produces hardly any by-products. Chemists should now be able to modify the pathway to make molecules that have slightly different structures from the toxin. By studying how brevetoxin B and its close chemical relatives interact with living cells, biologists may be able to work out exactly why it is poisonous. With this knowledge, it may be possible to devise a way of blocking its toxic effects.

Analysts could also use the large quantities of brevetoxin B that can now be made in the laboratory to test a chemical sensor for the toxin. This could eventually lead to a method for screening shellfish, to ensure that they are not dangerously contaminated with the Poison (see Diagram).